DESCRIPTION: Loss of optic nerve axons and the development of optic nerve head cupping are common to all forms of glaucoma. Recent studies have identified increased matrix metalloproteinases (MMPs) within the glaucomatous optic nerve head. As MMPs are known mediators of tissue remodeling, this could be important in the mechanism of optic axon loss and gliosis that occur in glaucoma. We have developed methods to measure mouse intraocular pressure and to produce chronic elevation of lOP in the mouse eye that induces optic nerve axon loss. We propose to use this experimental system to characterize MMP changes in the retina and at the optic nerve head following lOP elevation and to determine their relationship to optic nerve axon loss and gliosis. Key in these studies will be the use of transgenic mouse models to investigate mechanisms of MMP regulation and substrates of MMP action. SPECIFIC AIMS: 1. To directly determine the identity and time course of MMP changes at the mouse optic nerve head following experimental lOP elevation. These studies will analyze MMP gene expression, protein expression and enzymatic activation. 2. To determine if the absence of MMP inhibition by endogenous inhibitors will increase optic nerve axon loss and increase gliosis in the optic nerve following experimental ocular hypertension. These studies will investigate TIMP-1 knockout mice and TIMP-2 knockout mice. 3. To determine if inhibition or elimination of MMP activity will reduce optic nerve axon loss and reduce gliosis in the optic nerve following experimental ocular hypertension. These studies will investigate MMP-9 knockout mice and a drug that inhibits MMP activity.